Alzheimer's disease (AD) is believed to result from an abnormal processing of the amyloid precursor protein (APP) leading to the formation of "toxic products" (TP). A growing appreciation exists not only of the role that the immune system plays in response to TP but that immunomodulation may prove to be a viable approach to AD treatment. Unfortunately, uncertainty remains about the exact role of the immune system in AD. Recently it has become apparent that T cells, found in increased numbers in AD brains, can regulate microglia activation and function. The goal of this proposal is to assess the role of T cells in the pathology of a unique rat model of AD developed in our laboratory. This model (TgF344-19+ or AD) is based on over-expression of two human genes, APPswe (K670N, M671L) and PS1?E9 (a deletion in the exon 9 Presenilin 1 gene), each an independent dominant cause of AD, that are inserted as transgenes on an F344 background. The AD rats show substantial amyloid deposition and behavioral abnormalities. In addition we have found that by 15 mo. there is a greater number of CD8+ T cells in the brains of AD animals compared to their wild-type (TgF344-19- or WT) littermates. Moreover, whereas the number of CD8+ T cells in the brain is correlated with the number in the spleen in the F344 background strain and in WT, the number of CD8+ T cells in the AD rats is not. We will use the TgF344-19+ model to assess the origin and importance of these CD8+ T cells with respect to AD pathology. Our working hypothesis is that TP provide a signal that allows for CD8+ T cell entry and clonal expansion in the brain. We believe the net effect of their presence is to lessen amyloid burden. We will evaluate this hypothesis in 3 sets of experiments conducted in parallel. The first set will measure behavior and CD8+ T cell numbers in brains of AD and WT at different ages. The second set will determine whether CD8+ T cells show preferential entry, clonal expansion or increased survival in brains of AD rats by studying the number and intensity of CFSE-labeled autologous CD8+ T cells following i.v. injection. The third set will use animals that lack a thymus and functionally mature immunocompetent lymphocytes of T cell lineages by virtue of homozygosity for the Rowett New mutation (rnu/rnu). AD and WT animals heterozygous and homozygous for the rnu mutation will be generated and evaluated for brain CD8+ T cells and behavior. Successful completion of the proposed study will establish the origin of these CD8+ T cells, when their increase takes place in relation to amyloid burden, and whether the T cells work to modify the severity of AD pathology and resulting behavioral abnormalities. Collateral determinations of cell biomarkers and cytokines will allow an initial assessment of how CD8+ T cells achieve this effect. By learning more about the function of CD8+ T cells in AD our results should provide the basis for the development of new treatments. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is believed to result from an abnormal processing of the amyloid precursor protein. There is, however, a growing appreciation not only of the role that the immune system plays in response to this abnormal processing, but that modifying the immune system response may prove to be a viable approach to treatment. Recently it has become apparent that T cells, another cellular component of the immune system, may play an important role in regulating microglia activation and function. Successful completion of the proposed study will establish the origin of the increased number of T cells found in the brains of Alzheimer patients, when the increase in T cells takes place in relation to the course of the development of AD pathology, and whether the T cells work to increase or decrease the severity of AD pathology and resulting behavioral abnormalities. By learning more about the function of these T cells and how to modify their affects in our rat model, our results should open up new pathways for treatment development.